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Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas
Angela Yoo1, Cerise Tang2, Mark Zucker3
1Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; SUNY Downstate Health Sciences University, Brooklyn, NY, USA; Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Background:
Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes.
Objective:
To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC.
Design, Setting, And Participants:
We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH.
Outcome Measurements And Statistical Analysis:
Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors.
Results And Limitations:
Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC.
Conclusions:
Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities.
Patient Summary:
Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities.
Insights
Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers. Despite a shared genetic cause, these distinct entities exhibit unique genomic and metabolic profiles, aiding in identifying previously unrecognized SDH-deficient RCC.
Area of Science:
- Oncology
- Genetics
- Metabolomics
Background:
- Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers.
- These cancers arise from the loss of key enzymes in the tricarboxylic acid (TCA) cycle.
Purpose of the Study:
- To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC.
- To identify distinct molecular features differentiating these rare kidney cancer subtypes.
Main Methods:
- Analysis of 42 tumors (25 FHRCC, 17 SDHRCC) using immunohistochemistry and genomic sequencing.
- Somatic alterations identified via clinical pipelines and FACETS for copy number alterations.
- Mass spectrometry-based metabolomic profiling performed on available tumor samples.
Main Results:
- Germline analysis revealed SDHB alterations in 16/17 SDHRCCs and FH variants in 17/22 FHRCCs.
- SDHRCCs showed lower mutation and CNA burden compared to FHRCCs.
- Both subtypes accumulated guanine; FHRCCs had elevated urea cycle metabolites, while SDHRCCs showed increased acylcarnitines, enabling identification of a novel SDH-deficient RCC subtype.
Conclusions:
- SDHRCC and FHRCC, despite a similar genetic etiology, are distinct molecular entities.
- Unique genetic and metabolic abnormalities characterize each subtype.
- Metabolic profiling can aid in classifying and identifying rare kidney cancer subtypes.
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